[2] With its southern border at what would be a continuation of the Mason-Dixon line to the Ohio River, it forms the base of the Northern Panhandle of West Virginia.

Marshall County is home to the largest conical burial mound in North America, at Moundsville.

Another major trail, more distinct in this area and proceeding east–west, was sometimes known as Braddock's Road or Nemacolin's Path after the native chieftain and trailblazer who assisted General Braddock and George Washington during their unsuccessful march through the Cumberland Narrows pass in the Appalachian Mountains seeking to capture Fort Duquesne in 1755.

The French explorer Sieur De la Salle had traveled on the Ohio River in 1669, and Captain deBlainville had buried lead plates staking France's claim to the valley in 1749.

English speakers attempted to strengthen their claims initially by settlement, much to the displeasure of local Native Americans.

The British government prohibited colonists from officially settling in the area in the 1763 peace treaty following that war.

John Wetzel staked a claim along Wheeling Creek in what is now Marshall County's Sand Hill District in 1764 (building a fortification by 1769).

The British concluded the Treaty of Fort Stanwix with the Iroquois in 1768, which purported to give them this area and much of the Ohio River valley, despite the claims of other native peoples, particularly the Algonquian-speaking tribes.

Joseph, James and Samuel Tomlinson built a cabin on the Flats of Grave Creek at what became Moundsville around the same time, but experienced "Indian troubles" upon returning the following spring, and despite fortifying it, left until 1773.

In the only pitched battle of that war (considerably downstream of Marshall County), Virginia militia led by colonel Andrew Lewis defeated outnumbered native warriors led by Shawnee Chief Cornstalk at the Battle of Point Pleasant on October 10, 1774.

In 1776, the Virginia General Assembly created the counties of Ohio, Monongalia and Yohogania from what had been the District of West Augusta.

It also negotiated its border with Maryland, and only ceded the area south of the Mason–Dixon line to the United States in 1787, when Virginia ceded its claims north of the Ohio River as well, allowing the Continental Congress to establish the Northwest Territory from the area west of both states' reduced claims.

The National Road received additional impetus when the Wheeling Suspension Bridge across the Ohio River was completed in 1848, although by this time railroad and steamboat technology had improved and superseded the roadway.

It was named in honor of John Marshall, Chief Justice of the United States Supreme Court, who died that year.

Jacob Burley, Benjamin McMechen, John Parriott, Samuel Howard and Zadock Masters became the new county's first Justices of the Peace, and Elbert H. Caldwell was selected as first Commonwealth attorney.

[14] Agriculture was the main industry during the first decades of Marshall County history, but trade continued along the Ohio River and the National Road.

An iron forge was established at Benwood near the Ohio river and Wheeling/Ohio County border in 1850, and that industrial area would develop following the Civil War.

Although both towns and the railroad proposed a bridge linking Benwood and Bellaire, Ohio long before, litigation by the pre-existing ferry company as well as the Civil War discussed below, meant the bridge was not completed until 1870, although refurbished, the B & O Railroad Viaduct remains in use today and was listed on the National Register of Historic Places in 1976.

[21] Marshall County was initially divided into nine townships: Cameron, Clay, Franklin, Liberty, Meade, Sand Hill, Union, Washington, and Webster.

[22] In 1866, after prisoners escaped from local jails, West Virginia's legislature authorized the purchase of land in Moundsville for the new state's penitentiary.

The wooden structure was replaced by a gothic-style stone and brick building (West Virginia Penitentiary now operated as a tourist attraction), probably modeled upon a facility opened in 1858 in Joliet, Illinois.

It remained West Virginia's maximum security penitentiary from 1876 until 1995 (with a section for female inmates until construction of a separate facility in the 1940s).

The U.S. Army Corps of Engineers had dealt with flooding on the Ohio River as interference to navigation long before the American Civil War, and in 1870 adopted a plan for construction of 13 locks and dams between Pittsburgh and Wheeling, and a few years later Congress authorized funding of a new prototype with adjustable gates near Pittsburgh to secure a 6-foot water flow.

The McMechen Lockmaster Houses on the Ohio River (built in Marshall County in 1911) are among the few that remain (and have been listed on the National Register of Historic Places since 1992).

[22] In the late 19th century, several industries, including manufacturers of brooms, buggy whips, bricks, building supplies, steel and glassware developed in Marshall County.

Industries which developed locally in the early 20th century included: paper box manufacturing, building materials, pottery, well-drilling tools, women's clothing, guns, and chemicals (in World War II).

[23] In 1924, Marshall County elected the first woman to serve as a West Virginia legislator, Dr. Harriet B. Jones.

On August 4, 1927, Charles Lindbergh landed near Moundsville, and by the decade's end the Fokker Aircraft Company established a plant, which became a major employer in the area, and in 1934 was transformed into a toy factory (which closed in 1980).